Anticancer Compounds Show Potential in Schizophrenia

Megan Brooks

April 03, 2014

Experimental p21-activated kinase (PAK) inhibitors reversed schizophrenialike behaviors and restored some lost brain function in a mouse model of schizophrenia.

Researchers from the United States and Japan engineered mice to carry the mutant disrupted-in-schizophrenia 1 (DISC1) gene, which leads to synaptic deterioration akin to that seen in schizophrenia.

They found that their PAK inhibitors not only significantly ameliorated the synaptic deterioration triggered by DISC1 knockdown but also partially reversed the size of deteriorated synapses.

The beneficial effects were seen at "very low concentrations of the inhibitors with virtually no toxicity," report lead author Akira Sawa, MD, PhD, professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine in Baltimore, and colleagues.

The study was published online March 31 in Proceedings of the National Academy of Sciences.

The researchers note that aberrant synpatic "pruning" during adolescence is believed to play a role in the pathology of schizophrenia. In line with this hypothesis, studies have shown dynamic changes in brain morphology and glutamate signaling in people with recent-onset schizophrenia and in those with prodromal stages of schizophrenia.

In the current study, using 2-photon spine imaging, the researchers showed that administration of a PAK inhibitor called FRAX486 in adolescent mice is "sufficient to block deteriorating spine loss and effective in preventing an adult behavioral deficit associated with schizophrenia."

"By using this compound to block excess pruning in adolescent mice, we also normalized the behavior deficit," Dr. Sawa, who is director of the Johns Hopkins Schizophrenia Center, said in a statement. "That we could intervene in adolescence and still make a difference in restoring brain function in these mice is intriguing."

"Drugs aimed at treating a disease should be able to reverse an already existing defect as well as block future damage," Dr. Sawa added. "This compound has the potential to do both."

"The efficacy of PAK inhibitors may have implications in drug discovery for schizophrenia and related neuropsychiatric disorders in general," the authors conclude in their article.

They note that pharmacologic PAK inhibition, which is being tested for anticancer activity, has been shown to protect against synaptic deterioration in an animal model of fragile X syndrome. Several lines of evidence have suggested the involvement of PAKs in Alzheimer's disease and mental retardation.

The research was supported by grants from the National Institute of Mental Health, the Stanley Foundation, the RUSK Foundation, the S-R Foundation, the National Alliance for Research on Schizophrenia and Depression, Johns Hopkins Medicine's Brain Science Institute, the Maryland Stem Cell Research Fund, the Japan Society for the Promotion of Science, PRESTO, and the Howard Hughes Medical Institute. The authors report no relevant financial relationships.

Proc Natl Acad Sci. Published online March 24, 2014.

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